This searchable list includes the abstracts of all presentations given at a conference organised as part of the SENS series. We regret that the videos recorded at SENS3 and SENS4 are currently unavailable.
Mitochondrial decay, (a decrease in membrane potential, respiratory control ratio, cardiolipin, and cellular oxygen consumption, and an increase in oxidant by-products) appears to be a major contributor to aging and associated degenerative diseases. Oxidative damage to DNA, RNA, proteins, and lipids in mitochondrial membranes is a major consequence of this decay, resulting in functional decline of mitochondria, cells, and organs. Feeding the mitochondrial metabolites acetyl carnitine and lipoic acid to old rats rejuvenates the mitochondria and improves brain and other function.Keywords: Degenerative diseases, Brain, Micronutrients, Cancer, Adaptive immunity
Appreciating the Designs of the Blind Watchmaker: How characterization and creation are creating a new biological engineering science.
There is a philosophical danger in using the language of engineering to describe the patterns and operations of the evident products of natural selection. Invoking principles of design runs the risk of invoking a designer. But as we analyze the increasing amount of data on the genome and its organization across a wide array of organisms we are discovering there are patterns and dynamics reminiscent of designs that we, as imperfect human designers, recognize as serving an engineering purpose including the purpose to be designable, or rather, evolvable.
Regenerative medicine can be defined as efforts to change the default mechanism of mammalian wound healing from one of inflammation and scarring to regeneration of injured or missing tissues. Such a therapeutic approach represents a dramatic paradigm shift in the practice of medicine. What factors facilitate the development of effective regenerative medicine strategies?
One basic quality of human life is that every time our cells divide the tips of our chromosomes get shorter. This shortening of telomeres may be the molecular clock of aging. Indeed, the shortening of telomeres has been shown to be the trigger that induces senescence of human cells grown in culture; whether this can be extrapolated to include human organismal aging itself is not yet known. The correlation between telomere length and age is very strong and shorter telomeres directly correspond to shorter human life expectancy, but "cause and effect" are still debated.
The inability to maintain telomere length in normal human cells lacking human telomerase (hTERT) activity results in cellular aging or replicative senescence. The identification of small molecules that induce telomerase activity in these normal cells may be useful for basic research aimed at studying telomerase regulation. Additionally, molecules found to induce hTERT expression, with high target selectivity, can possibly be used in therapeutic applications directed to alleviate or delay symptoms of aging. A high throughput screening (HTS) effort by Sierra Sciences L.L.C.
Cellular senescence is a crucial tumor suppressive mechanism that prevents the proliferation of cells at risk for neoplastic transformation. Numerous potentially oncogenic stimuli can induce a senescence response, which causes cells to enter a stable and essentially irreversible growth arrested state. Senescent cells are metabolically active and secrete myriad inflammatory cytokines, growth factors and other molecules that can alter the local tissue microenvironment. Senescent cells have been shown to accumulate with age and at sites of age-related pathologies.Keywords: Cancer, DNA damage signaling, Inflammation, Matrix metalloproteinases
Caenorhabditis elegans lifespan is profoundly modulated by its diet of E. coli: What are the roles of E. coli metabolism and coenzyme Q?
Coenzyme Qn is a fully substituted benzoquinone containing a polyisoprene tail of distinct numbers (n) of isoprene groups. Q is an essential component of respiratory electron transport and a potent lipid soluble antioxidant. Extended lifespans are observed in C. elegans clk-1 mutants with defects in Q biosynthesis. Intriguingly, mice heterozygous for a clk-1 gene disruption also show increased lifespan. C. elegans fed E. coli devoid of Q8 have a significant life span extension when compared to C. elegans fed a standard Q-replete E. coli diet.Keywords: Coenzyme Q, Ubiquinone, Dietary restriction, Caenorhabditis elegans
While the underlying reasons and molecular mechanisms of physiological aging are not identical in various adult organ systems, one common characteristic is insufficient or failed regenerative processes. This age-specific lack of tissue repair, which leads to degeneration and loss of function, is perfectly exemplified in skeletal muscle and we are attempting to understand this aging process in cellular and molecular terms.Keywords: Muscle stem cell, Niche aging, Signal transduction
Optimized allotopic expression of mitochondrial genes: a strategy for treating mitochondrial DNA diseases
Mitochondrial diseases due to mutations in mitochondrial DNA can not be ignored anymore in most medical areas. With prevalence certainly higher than one in 6000, they probably represent the most common form of metabolic disorders. Despite progress made in identification of their molecular mechanisms, little has been done regarding therapy. We have recently optimized the allotopic expression for the mitochondrial genes ATP6, ND1 and ND4 and obtained a complete and long-lasting rescue of mitochondrial dysfunction in human fibroblasts in which these genes were mutated.Keywords: Mitochondrial DNA, Allotopic expression, mRNA sorting to the mitochondrial surface, Optic neuropathies, Gene therapy
Accumulation of altered proteins and damaged organelles is a characteristic common to most types of cells and tissues in old organisms. Although often at a very slow peace, this progressive accumulation often compromises important cellular functions and eventually becomes detrimental and leads to cell death. Cells count on two surveillance systems to handle protein alterations: chaperones and proteolytic systems. Malfunctioning of these systems contribute in large extend to the abnormal accumulation of those altered proteins in cells and tissues in numerous diseases and in aging.Keywords: Autophagy, Proteases, Lysosomes, Chaperones
Why don't intentional exposures to known carcinogens, such as cigarette smoking, always cause lung cancer for most people? Living well into very old ages with heavy smoking but without getting lung cancer is not likely due to just being lucky. It is highly likely that most humans are protected intrinsically by an innate mechanism to confront cancer cells. If cancer is associated with a decline of such a protection mechanism, restoring this activity may offer a new avenue for cancer treatment.Keywords: Cancer resistance, Granulocyte, Cancer therapy, Clinical trial, LIFT
The key physiological characteristic of aging is a failure to maintain tissue integrity due to progressive deterioration, coupled to the apparent exhaustion of normal regenerative potential. This may be due to environmental factors, such as DNA damage, which eventually cannot be overcome, and/or genetic components may exist that enforce intrinsic processes within an individual. We are developing a new model organism to study aging in which both characteristics are present and can be experimentally manipulated: an ascidian, or sea squirt, called Botryllus schlosseri.
Reduced function of T lymphocytes has been implicated in the age-associated increased morbidity and mortality due to infections as well as in the enhanced risk of cancer. Like other normal human cells, T lymphocytes are limited in their proliferative potential. Cell culture studies of repeatedly stimulated T cells have identified a variety of phenotypic, genetic and functional changes associated with the end stage of replicative senescence.
The many observable signs of human senescence have been hypothesized by various researchers to result from several primary causes. Close inspection of the biochemical and physiological pathways associated with age-related changes and with the hypothesized causes reveals several parallel cascades of events that involve multiple interactions and feedback loops. We present a network diagram to aid in conceptualizing the many processes and interactions among them, including promising intervention points for therapy development.Keywords: Pathways, Causes, Systems, Flowchart, Network
A Cell-Based, High Throughput Screening Assay to Identify Small Molecule Compounds that Derepress Endogenous hTERT Expression Using Toxic hTR Template Mutants
Human telomerase is the subject of intense research because of its critical function in cellular immortality via telomere length maintenance. Presence of telomerase activity is strongly associated with immortality of embryonic stem and cancer cells. The human telomerase complex is composed of the human Telomerase Reverse Transcriptase protein (hTERT) and the human Telomerase RNA (hTR). Expression of telomerase activity is controlled, mainly at the level of hTERT transcription. However, the specific mechanisms of repression or silencing of the hTERT promoter region remain unclear.
Cardiovascular disease and osteoporosis are leading health care problems in our aging population. Numerous studies have documented an association between these two multifactorial and degenerative diseases. Moreover, atherosclerosis is considered to be a chronic inflammatory disease such that the immune system actually modulates the atherogenic process. In addition, the immune system plays a key role in bone resorption through production by activated T lymphocytes of RANKL (receptor activator for NFkB ligand), a protein that stimulates the maturation and activity of osteoclasts.Keywords: Atherosclerosis, Osteoporosis, T cells
Age is the single most important risk factor for cancer and every strategy for postponing human senescence ultimately relies on developing efficient ways of eradicating neoplastically transformed cells from the body. Although conventional treatments have been improved against primary tumors, they are less effective against metastases. Indeed, most cancer patients do not die from the primary tumor, which can be effectively diagnosed and removed, but as a result of metastasis.
A Cell-Based, High Throughput Screen to Identify Small Molecule Compounds that Derepress the Telomerase Minimal Promoter in a Transient Luciferase Expression System
The presence of telomerase activity in human cells is strongly correlated to the expression of hTERT which is repressed in normal adult human cells. We are undertaking a screen for compounds that activate telomerase expression using a transient expression system similar to the one previously described by Won et al. The telomerase minimal promoter sequence was inserted into a promoter-reporter plasmid to drive expression of the luciferase coding sequence.
Caleb Finch at USC coined the term "negligible senescence" in 1990; later he added the test criteria of no observable age-related increase in mortality rate or decrease in reproduction rate after maturity, and no observable age-related decline in physiological capacity or disease resistance. AgelessAnimals.org (a.k.a. Centenarian Species and Rockfish Project), has previously studied rockfish and turtles in 14 pilot studies, twelve in the U.S. and two in Europe.Keywords: Negligible senescence, Ageless, Whales, Rockfish
Diminished immune function and chronic inflammation are hallmarks of aging. They are also the major cause of morbidity and mortality associated with increasing age. The underlying causes for the same are not well understood. Here we show the increased reactivity of dendritic cells from aged subjects to self antigens as a potential mechanism contributing to age-associated inflammation. Consistent with this, dendritic cells from aged subjects display increased reactivity to intracellular self DNA by secreting enhanced quantities of type I interferon and IL-6 compared to the young controls.Keywords: Dendritic cells, Self DNA, Inflammation
Human embryonic stem (hES) cells are being studied as potential source of cells for the treatment for many diseases (e.g. diabetes, Parkinson's, leukemia, congestive heart failure). The successful integration of hES cells into such therapies will hinge upon three critical themes: stem cell expansion in number without differentiating (i.e., self-renewal); differentiation into a specific progenitor type or collection of cell types; and, promotion of their functional integration into existing tissue.
Telomeres are chromosomal caps that prevent genomic instability and protect chromosomal integrity. When cells divide, telomeres shorten due to the "end replication problem". Decreased telomere length is associated with cellular senescence (aging), as older cells show markedly shorter telomeres. A predominant hypothesis between telomere length and aging is that the relationship is causative rather than correlative, i.e. decreased telomere length causes aging, or at least several of the main symptoms of it.
There is a growing consensus that the costs of intellectual property rights threaten to undermine the very progress these rights are intended to promote. Particularly in biotechnology, where innovation depends on integrating complex chains of components, royalty stacking and "patent thickets" surrounding key technologies can cause an entire field to stagnate (eg the WARF patents). In the past 30 years, the life sciences have failed to deliver on their promise, with only a few "lottery winners" such as Amgen and Genetech, amidst a sea of "losers" that never turn a profit.Keywords: Open Source Biotechnology, Patents
Rhodiola rosea is an adaptogenic plant that can increase the resistance of an organism to physical, mental and environmental stresses. Previously, we found that R. rosea could extend the mean life span of the fruit fly, Drosophila melanogaster, approximately 7%. We evaluated a new formulation of R. rosea (SHR-5) which contains elevated levels of the putative active compounds (rosin, rosarin, and rosavin), and found that it could extend mean life span by 43% (P<0.0001), and maximum life span by 33% when compared to control diet fed flies. The precise mechanism of R.Keywords: Rhodiola rosea, Drosophila, Lifespan, Anti-oxidants, Oxidative stress
Tissue stem cells reside in specialized microenvironments, or niches, that strongly influence stem cell behavior to maintain the appropriate balance of stem and progenitor cells available for tissue homeostasis and repair. The germline stem cell (GSC) niche in the Drosophila male gonad is located at the apical tip of the testis where stem cells are in contact with the hub, a cluster of approximately 10-15 somatic cells that secrete the key self-renewal factor unpaired (upd).Keywords: Stem cells, Niche, Germ line, Drosophila
A novel technique of flow measurement using thermistor with real time graphical display for anaesthesia ventilator
Anaesthesia ventilator is a life saving device that is quite useful in clinical applications under general anaesthesia giving respiratory support during various surgeries in the operation theatres. When respiration takes place, flow at different points of the respiratory tract changes.Keywords: Anaesthesia ventilator, Flowmeter, Gas flow rate, Mass flow controller, Thermistor
The gradually loss of the proliferative capacity in fibroblasts and other cells in vitro may be a manifestation of cellular maturation and terminal differentiation but not of the true senescence of cells. The limitless proliferative potential which somatic stem-like cells are thought to possess is clearly revealed by means of in vitro restoration of the stem cell supporting microenvironment, or by removing differentiating stimuli from the cell culture, or by adding differentiating inhibitors to cultural medium, etc.Keywords: Cellular non-senescence, Rate of aging, Environmental influence
Gene Expression Profiling of MRC5 Lung Fibroblasts Treated with TA-65 and C0057684 using DNA Microarrays
The majority of cancer cell lines and human embryonic stem cells express the catalytic subunit of telomerase reverse transcriptase (hTERT), which maintains chromosomal ends through the addition of telomeric repeats. In normal somatic cells, telomerase transcription is repressed and the erosion of telomeres limits replicative lifespan and leads to cellular senescence. Transient pharmacologic activation of hTERT has the potential to delay senescence and extend human lifespan. TA-65, a natural compound derived from the Chinese herb Astragalus and licensed to T.A.
Targeted Nanoparticle Probes for Identifying, Tracking and Isolating Embryonic Stem Cell Derived Progenitor Cells
Pluripotent stem cells whether from embryonic (ES) or induced (iPS) cells offer a potentially unlimited source of replacement cells for treating human degenerative diseases associated with aging such as cardiovascular disease, macular degeneration, aging skin, diabetes, Parkinson's, and Alzheimer's disease. The availability of iPS cells will no doubt increase the number of research grade ES-like cell lines dramatically and may ultimately fulfill the need for patient specific stem cells.Keywords: Embryonic stem cells, Peptide targeting, Progenitors, Quantum dots, Phage display
Mitochondrial dysfunction, oxidative stress and apoptotic cell death are fundamental mechanisms that drive mammalian aging. Iron (Fe) mediated redox chemistry is particularly important because of its role in mitochondrial oxidative phosphorylation and other life-sustaining functions. Perturbation of mitochondrial Fe homeostasis causes a decline in mitochondrial function and plays a significant role in various neuromuscular degenerative diseases, as well as age-related tissue dysfunction.Keywords: Mitochondrial iron homeostasis, Mitochondrial permeability transition pore, Mitochondrial RNA, Oxidative stress, Skeletal muscle subsarcolemmal and interfibrillar mitochondria
Rapidly increasing data on completely sequenced mitochondrial DNA (mtDNA) in different species provide a possibility for comprehensive analysis of the relationships between mtDNA and longevity. We have recently shown that GC content of mtDNA and resting metabolic rate are two powerful predictors of mammalian longevity, which together explain more than three fourths of variation in maximum life span (MLS).Keywords: mtDNA, Longevity, Mammals
Monitoring recovery of an aging cohort with an adaptive, Internet-based clinical trial, based on a molecular model of chronic disease
Based on this author's experience on an NIH monitoring board, we devised and conducted an Internet-focused, community-based, phase II clinical study of a VDR-agonist antibacterial therapy, which demonstrated proof of concept of a novel biological description of the chronic disease process. We collected evidence that restoring competence of the innate immune system will reverse the progression of much chronic disease.Keywords: Chronic disease, Adaptive study, Internet study
In 2006 we reported routinely inducing recovery from chronic inflammatory disease, including 'autoimmune' syndromes. In 2008 we additionally reported inducing recovery from chromic neurological disease, including neuropathies, cognitive and memory deficiencies, depression, Bipolar and Obsessive Compulsive Disorders.Keywords: VDR, Chronic disease, Microbiota
Telomerase is a specialized ribonucleoprotein complex, consisting of a telomerase reverse transcriptase protein component (hTERT) and an RNA component (hTR), which adds telomeric TTAGGG repeats at the chromosome tips. Telomerase is expressed in stem cells, germ cells, cancer cells and some rapidly proliferating cells while being undetectable in most somatic cells. The lack of telomerase expression in normal somatic cells leads to cellular aging and senescence due to telomere shortening.
Fingertips in humans and toetips in rodents have the ability to regenerate after amputation injury. We have developed the regenerating toetip in mice as a model for eipmorphic regeneration in a mammal. During toetip regeneration a blastema of proliferating cells accumulate at the amputation site. These cells re-express genes that are known to play a critical role both in digit tip development and in digit tip regeneration in the embryo. The blastema eventually grows out and differentiates to form the distal region of the terminal phalangeal bone and surrounding connective tissue.Keywords: Epimorphic regeneration, Mouse, Bone, Fibroblasts
In the rapidly emerging field of anti-aging medicine, predictions have provided the scaffold around which the field is evolving, being contested, and practiced. While contemporary anti-aging clinical practice is hotly debated and often derided, the research and hope for future therapies has captured a great deal of public and scientific interest in the past decade. Many anti-aging proponents foresee a not-so-distant future in which the process of aging itself will be retarded, stalled and perhaps even reversed.
Increased proportions of CD8 T cells lacking expression of the CD28 co-stimulatory receptor and having short telomeres are associated with numerous deleterious clinical outcomes in the elderly, including decreased vaccine responsiveness and early mortality. Cells with a similar phenotype arise in cell culture following multiple rounds of antigen-driven proliferation. In addition to the cell cycle arrest and loss of CD28 expression, senescent CD8 T cells secrete high titers of the pro-inflammatory cytokine, TNFalpha.Keywords: Senescence, CD28, TNFalpha, Caspase-3
A sensitive method of Nested PCR for the detection of low copy number human telomerase reverse transcriptase mRNA
The human telomerase gene (hTERT) is repressed in normal human cells, resulting in telomere loss, and ultimately cellular aging. The identification of C0057684, a small molecule shown to activate hTERT expression in normal human fibroblast cells, has given us a valuable tool to optimize hTERT detection by RT-PCR in normal human cells. However, conventional TaqMan RT-PCR methods are not amenable to analyzing compounds that are weak inducers of hTERT. Nested PCR is commonly used to amplify low copy number targets where high levels of sensitivity and specificity are needed.
The VDR nuclear receptor is at the heart of human innate immunity, being responsible for expression of a majority of the body's antimicrobial peptides. Chronic inflammatory disease causes VDR dysfunction, with ripple-down effects on the Thyroid, Glucocorticoid, Androgen and Progesterone nuclear receptors. This VDR dysfunction inhibits the innate immune system from expressing most of its antimicrobial peptides, allowing viral and bacterial metagenomic communities to evade phagocytosis, and become persistent pathogens.Keywords: VDR, Chronic disease, Immunology
Several major age-related diseases are associated with the long-term accumulation of pathogenic materials (i.e., "junk") within and between our bodies' cells: e.g., atherosclerosis (oxidized cholesterols in the artery wall), macular degeneration (fluorophores of the retinal pigment epithelial lipofuscin), and extracellular matrix dysfunction (advanced-glycation end-products in long-lived proteins). Medical bioremediation is a strategy to remove these accumulations from affected cells by using catabolic enzymes derived from environmental microorganisms.Keywords: Medical bioremediation, Atherosclerosis, Macular degeneration
New molecular therapies based on stem cells and gene delivery have significant potential for tissue engineering and repair for numerous diseases. Before these approaches can succeed, however, a number of fundamental engineering challenges must be overcome, particularly in the nervous system, our tissue of interest.Keywords: Neural stem cell, Adult neurogenesis, Biomaterials, Viral vector
Unfocused Pulsed Lasers Selectively Destroy Lipofuscin - Using An Established Technique To Repeatedly Postpone Aging
Lipofuscin accumulates in the lysosomes of aging post-mitotic cells and progenitor cells, interfering with autophagy. Thus it has been proposed that the removal of this indigestible aging pigment may be a highly effective rejuvenation therapy. While current gene therapy experiments involving xenoenzymes look promising, there are still several drawbacks to such an approach, and the extent of therapeutic benefit remains to be seen. However, even though the lysosome uses enzymes to degrade its contents, this is not the only method known to modern science.Keywords: Lipofuscin, YAG, Laser, Photothermolysis
Rhodiola rosea root has long been used in the traditional medical systems in Europe and Asia as an adaptogen to increase an organism's resistance to physical stress. Recent clinical research has demonstrated its ability to improve mental and physical stamina, to improve mood, and to help alleviate high-altitude sickness. We have also recently found that R. rosea (SHR-5) is able to extend both mean and maximum life span of Drosophila melanogaster. The mode of action of R. rosea is currently unknown; however, it has been proposed to act as an antioxidant.Keywords: Rhodiola rosea, Oxidative stress, Anti-oxidants
Ectopic expression of human telomerase (hTERT) produces telomerase activity and circumvents telomere-based replicative aging in normal cells. We have used hTERT to immortalize a variety of human cell types. Corneal epithelial cells expressing introduced hTERT require growth on collagen IV while both breast and skin epithelial cells require feeder layers to prevent a premature p16-induced growth arrest due to inadequate culture conditions. Human corneal and skin cells expressing hTERT can be used to form organotypic (3D) cultures that may be useful for regenerative medicine.Keywords: Cancer, Tissue engineering, Telomeres, Aging
Optimal nutrition is important for humans of any age. Yet a number of changes occur in the gastrointestinal tract throughout the lifetime of an individual including changes in the intestinal morphology and in the absorption of nutrient substances. In older people, these alterations can significantly decrease intestinal function and contribute to undernutrition or malnutrition. In diseased individuals, medical illnesses and surgical operations may further restrict or even eliminate the ability to absorb nutrients and vitamins in sufficient quantities.Keywords: Intestine, Bioengineering, Malabsorption, Human
Soft Tissue Regeneration of Infected Wounds Following the Use of Microcurrent as the Sole Therapeutic Modality
It has long been recognized that in addition to the massive and complex biochemical and cellular response that occurs as a result of significant injury, tissue repair and regeneration is dependent on highly specific changes in electrical fields at the site of damage. These changes generate what has been called a micro current of injury and effect the up-regulating of an array of growth factors and cytokines within the intracellular matrix.Keywords: Tissue regeneration, Microcurrent, ATP
The long term goal of Sierra Sciences LLC is to find a compound that induces telomerase activity for basic research purposes as well as anti-aging therapeutic applications. As a result of our cell-based high throughput screening effort utilizing a transient hTERT minimal promoter and luciferase reporter expression system, 929 compounds from a diversified small molecule library of over 123,840 compounds were found to induce luciferase expression. Cells treated with the active compounds from our primary screen are being examined for hTERT mRNA expression through real-time RT-PCR.
With chronic diseases or aging, stem cells or progenitor cells decrease in number and in function and with this decrease in positive cells, disease happens. Major diseases of aging include those where cells are known to fail: cardiovascular disease, diabetes, etc.
In the last fourth years, in all the industrialized countries the progressive decline of the mortality (1-2% year) in individuals over-80 years old has risen up of about twenty times the number of oldest old people. So centenarians are not more a curiosity, but in Europe are 1/10000 inhabitants. Moreover, it has been demonstrated that the children of centenarians, who are typically in their 70s and 80s, have a survival advantage when compared with age-matched controls whose parents died at an average life expectancy.Keywords: Centenarians, Immunosenescence, Longevity
There is extensive variability in age-related degeneration, both among different, genetically identical animals and among cells of the same type within an individual. Such stochasticity can be explained very well in the context of the idea that aging is ultimately caused by the accumulation of somatic damage. As dictated by evolutionary logic, all cellular processes evolve toward procreation, even at the expense of the soma (at least in most metazoans). This logically explains why somatic damage is allowed to accumulate, even to the extent that eventually it will bring life to a close.